The family Flaviviridae comprises three genera, the genus flaviviruses, the genus pestiviruses, and the genus hepaciviruses.
The genus flaviviruses mainly includes viruses transmitted by mosquitoes or ticks, many of which are important pathogens of humans, and also of animals. Particularly important are the yellow fever (YF) virus, the Japanese encephalitis (JE) virus, the four serotypes of dengue (Den) viruses, the tick-borne encephalitis (TBE) virus, and also the West Nile (WN) virus which recently has also appeared in North America as a pathogen in humans and in various bird species.
The genus of pestiviruses contains animal pathogens of great economic importance, i.e. the classical porcine fever (CPF) virus, the bovine viral diarrhoea (BVD) virus and the border disease virus (BDV).
The genus hepaciviruses comprises the different subtypes of hepatitis C virus (HCV) and related viruses, such as the hepatitis G virus (HGV).
These three genera are combined in the family of Flaviviridae, since all representatives of this family have a nearly identical genome structure and show agreement in numerous structural and functional properties. All flaviviruses are relatively small, enveloped viruses which comprise a single-stranded RNA molecule with mRNA polarity as genome. The genome has a long open reading frame that codes for all proteins in the form of a polyprotein. The individual mature virus proteins are formed by the activity of viral and cellular proteases. The arrangement of the individual virus proteins in the genome is the same for all flaviviruses and starts at the 5′ end with the capsid protein, the surface proteins and a series of non-structure proteins, the last of which is the viral polymerase. As a special feature, the pestiviruses furthermore contain an autoprotease in front of the capsid protein. The nucleocapsid of the flaviviruses is formed by just one single viral protein, i.e. the capsid protein, and surrounds the viral genome. The capsid is assumed to have an icosahedral symmetry.
The exact three-dimensional structure of the capsid protein is not yet known for any one of the flaviviruses. But the known amino acid sequences have numerous correlations, so that it is very likely that the capsid proteins will have numerous structural similarities. In this case, the similarities in representatives of the same genus naturally will be even greater than between representatives of different genera. In all instances, the capsid protein is a rather small protein having a length of approximately 100 to 190 amino acids. It has an unusually high portion of basic amino, acids, i.e. of the amino acids lysine and arginine. It is assumed that the basic amino acids are important for the interaction with the viral RNA (Khromykh and Westaway, 1996). Yet, all flavivirus capsid proteins also have characteristic hydrophobic sections (FIG. 1). Such a hydrophobic section always is formed by the carboxy-terminal approximately 20 amino acids. This section serves as an internal signal sequence for the surface structure protein following in the genome sequence. By this signal sequence which during protein syntheses is integrated in the membrane of the endoplasmatic reticulum, the capsid protein initially is anchored in the membrane. Later on, the anchor is proteolytically cleaved. In addition, there are internal hydrophobic sections. In representatives of the genus flaviviruses, the functional importance of an internal hydrophobic domain has been described (Markoff et al. 1997). The authors have indicated the borders of this domain for a series of flaviviruses as follows: dengue 1: 46-67, dengue 2: 46-66, dengue 3: 46-67, dengue 4: 45-65, Japanese encephalitis: 46-62, West Nile: 46-62, Murray Valley encephalitis: 46-62, Saint Louis encephalitis: 45-61, yellow fever: 43-58, Langat: 42-54, Powassan: 40-52, TBE: 42-54. Also for hepatitis C virus, a functionally important internal hydrophobic domain has been identified (Hope and McLauchlan, 2000), extending from amino acids 119 to 145, in particular from 125 to 144. Also pestiviruses have short internal sections of mainly hydrophobic character.